US9546159B2 - N-substituted 3,4-bis (catechol) pyrrole compounds, and the preparation and use thereof in the treatment of cancer - Google Patents

N-substituted 3,4-bis (catechol) pyrrole compounds, and the preparation and use thereof in the treatment of cancer Download PDF

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US9546159B2
US9546159B2 US14/435,768 US201314435768A US9546159B2 US 9546159 B2 US9546159 B2 US 9546159B2 US 201314435768 A US201314435768 A US 201314435768A US 9546159 B2 US9546159 B2 US 9546159B2
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compound
pharmaceutically acceptable
alkyl
cancer
following formula
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US20150344460A1 (en
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Pascal Collin
Maxim Egorov
Bernard Delpech
Joanna Bakala
Maria Achab
Jérome Bignon
Odile Thoison
Michel Benechie
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Centre National de la Recherche Scientifique CNRS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms

Definitions

  • the present invention relates to novel N-substituted 3,4-bis(catechol) pyrrole compounds, the preparation and use thereof in the treatment of cancer.
  • Tumour cells originate from innate or acquired chromosomal modifications resulting from translocation, genic amplification, retroviral insertion, mutation, genetic deletion, and epigenetic disorders. These anomalies affect numerous genes involved in controlling the cell cycle, apoptosis, growth and survival, and DNA repair and stabilisation and detoxification genes.
  • the large majority of conventional anticancer chemotherapy is essentially based on the use of drugs wherein the mode of action involves blocking cell multiplication, either in the S phase of the cell cycle by attacking cell DNA or in the G2/M phase by attacking the microtubules of the mitotic spindle required for cell division.
  • Further anticancer agents are intended to trigger programmed cell death by apoptosis, by inducing oxidative stress.
  • the drawback of these approaches is the relative non-specificity of the drugs which are unable to spare healthy cells. Multiple side-effects follow. More recently, novel therapeutic approaches have been developed no longer using a cytotoxic action, as the curing means, but rather the use of an impediment to slow down or stop tumour growth.
  • This targeted chemotherapy targets the intimate mechanisms of cell proliferation by blocking cell multiplication, by inhibiting growth factor signal transmission pathways, or by inhibiting angiogenesis.
  • chemoresistance differs from the known chemoresistance mechanisms essentially associated with drug expulsion membrane system expression: ABC (ATP-Binding Cassette) protein including the MDR1 (Multi Drug Resistance-1) system.
  • ABC ATP-Binding Cassette
  • MDR1 Multi Drug Resistance-1
  • cancer cells develop chemoresistance by stimulating the survival pathway, associated with pro-apoptotic pathway inhibition.
  • This survival pathway is activated by tyrosine kinase activity receptors (EGFR, PDGFR, IGFR), themselves activated by growth factors.
  • PI3K Phosphatidyl inositol 3 OH kinase
  • PDK phosphoinositide-dependent tyrosine kinase
  • Akt serine/threonine protein kinase PKB
  • PTEN phosphatase and tensin homologue deleted on chromosome 10
  • FOXO forkhead box O
  • mTOR mimmalian target of rapamycin
  • survival pathway inhibitors as an anticancer treatment may be considered as a new weapon against cancer.
  • the present invention relates to novel N-substituted 3,4-bis(catechol) pyrrole compounds having the general formula (I) hereinafter, the preparation thereof and the antimitotic action thereof and the mode of action thereof with respect to cancer cells.
  • the present invention particularly relates to the compound having formula (Ia) and the use thereof as a cancer treatment drug.
  • radicals R 1 and R 2 form, together with the nitrogen atom bearing same, a heterocycle which is saturated and does not comprise any other heteroatom than the nitrogen atom bearing R 1 and R 2 . More particularly, R 1 and R 2 form, together with the nitrogen atom bearing same, a 10- to 15-member, preferably 13-member, heterocycle.
  • the chain A is a saturated linear hydrocarbon chain comprising 3 to 6 carbon atoms, preferably 3 carbon atoms.
  • the present invention particularly relates to the compound having formula (1) or a pharmaceutically acceptable acid salt thereof.
  • the compound (1) used at concentrations encompassing the IC50 thereof, does not exhibit any cytotoxicity with respect to normal human cells.
  • the preferred pharmaceutically acceptable acid salt of the general formula (I), more particularly the compound (Ia) and preferentially the compound (1) is a hydrochloride.
  • the present invention also applies to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound having general formula (I), more particularly the compound (Ia) and preferentially the compound (1), with at least one pharmaceutically acceptable excipient.
  • the present invention relates to the use of the compounds (I), more particularly (Ia) and (1), as a drug in the treatment of cancer, in particular lung, breast, liver, stomach, colon, rectal, oesophageal, laryngeal, nasopharyngeal, pancreatic, prostate, kidney, bladder, duodenal, endometrial, pleural, skin, testicular, ovarian, uterine, brain, bone, oral, ocular cancer, or haematopoietic cancers such as leukaemias, myeloid leukaemias, lymphomas, bone marrow cancer or tumours of neuroectodermal origin such as glioblastomas.
  • cancer in particular lung, breast, liver, stomach, colon, rectal, oesophageal, laryngeal, nasopharyngeal, pancreatic, prostate, kidney, bladder, duodenal, endometrial, pleural, skin, testicular, ovarian,
  • the invention also relates to a process for preparing a compound having formula (I), more particularly (Ia) and (1) comprising:
  • n and m, EAG, R 1 , R 2 and A are as defined above with respect to the general formula (I), and X represents a halogen atom, to arrive at a compound having formula (I).
  • the halide (III) and the amine (II) are first allowed to react with one another before adding the aldehyde (IV).
  • the radical X of the halide (III) is a chlorine, bromine or iodine atom.
  • N-(3-aminopropyl)azatricyclodecane (2) ((a) G. Koren-Goldshlager, Y. Kashman, M. Schleyer, J. Nat. Prod., 1998, 61, 282-284; (b) D. E. Williams, K. S. Craig, B. Patrick, L. M. McHardy, R. van Soest, M. Roberge, R. J. Andersen, J. Org. Chem., 2002, 67, 245-258) was obtained from commercial laurolactam as per diagram 1 hereinafter:
  • a monotope formation method was developed for the synthesis of the pyrrole 5 from the amine 2, the halide 3 and the phenylacetaldehyde 4 (Diagram 3).
  • the corresponding hydrochloride was obtained by treating with a solution of HCl in methanol.
  • Phenacyl bromide 3 (1.23 g; 4.2 mmol) and NaI (3.2 g; 21 mmol) are added to a solution of amine 2 (1 g, 4.2 mmol) in DMSO (20 ml) at AT in argon and the reaction mixture is stirred for 15 min at AT.
  • a solution of aldehyde 4 (900 mg, 4.3 mmol) in methanol (60 ml) is then added and the reaction mixture is stirred for 16 hours at AT.
  • the cells selected for this study were incubated at 37° in the presence of compound (1) added in the culture medium at different concentrations and at different times.
  • the set of experiments conducted made it possible to determine the degree of toxicity of the compound under test, study the effect thereof on the progression of the cell cycle and the capability thereof of inducing an autophagic response and cell death by apoptosis.
  • the effect of compound (1) on HCT-116, U87 and K562 cell growth was evaluated using a cell growth test (CellTiter-BlueTM m Cell Viability Assay, Promega).
  • the growth curves and the IC50 values (concentration of compound inducing a 50% reduction of cell growth) determined after 72 hours of cell treatment with compound (1) are presented in FIG. 1 . They are 30 nm for HCT-116 cells, 45 nM for U87 cells and 70 nM for K562.
  • FIG. 2 represents the effect of compound (I) on the number and viability of HCT-116 cells as a function of the concentration thereof and the treatment time.
  • FIG. 2 a The results presented in FIG. 2 a demonstrate that the number of cells decreases as a function of the concentration thereof and the treatment time with compound (1).
  • Compound (1) at the 25 nM concentration already exhibits an activity from 24 hours of treatment by reducing the number of cells by 40%, reaching up to 80% inhibition from 48 hours for concentrations greater than the IC50. This inhibitory effect is however associated with a lack of modification of cell viability ( FIG. 2 b ). This indicates that the action of compound (1) is cytostatic and not cytotoxic.
  • IC50 values are thus up to 300 times higher for normal cells compared to those obtained for cancer cells. This clearly indicates that malignant cells are significantly more sensitive to the action of compound (1) compared to healthy cells.
  • JC-1 is a lipophilic anionic compound which selectively penetrates the mitochondria, the colour whereof changes from green to red when the transmembrane potential increases. Unlike healthy cells, cells in apoptosis exhibit a low ⁇ m which is associated with a strong green colour of the JC-1 probe.
  • the HCT-116 cells were treated with compound (1) at different doses for 24 hours.
  • the cell extracts then underwent Western Blot analysis in order to view the expression of the protein LC3-II.
  • the protein LC3 exists in the cell either in cytosolic form (LC3-I) or associated with phagosomes (LC3-II). The latter is the marker of the autophagic reaction.
  • FIG. 8 demonstrate that compound (1) blocks this survival pathway. Indeed, HCT-116 cells were exposed for 24 hours to the action of compound (1) at concentrations varying from 5 nM to 100 nm.
  • the Western Blot analysis of the cell extracts revealed that compound (1), from the 25 nm concentration, totally suppresses Akt protein serine 473 phosphorylation ( FIG. 8 a ). It stimulates the expression of the protein FOXO3 ( FIG. 8 b ), the synthesis whereof is reduced by the Akt-phosphorylated protein. It stimulates the expression of the protein peroxiredoxin 1, the gene whereof is described as being under the control of the FOXO3 factor ( FIG. 8 c ).
  • the protein peroxiredoxin is an enzyme having a peroxidase activity, controlling the intracellular hydrogen peroxide (H 2 O 2 ) concentration. Therefore, we evaluated the effect of compound (1) on the intracellular H 2 O 2 concentration, using DCF-DA (2′,7′-dichlorofluorescein diacetate, Sigma) as a marker of intracellular H 2 O 2 .
  • Hydrogen peroxide is an intracellular second messenger. It regulates, according to the concentration thereof, numerous functions such as proliferation or apoptosis. A reduction of the concentration thereof is associated with a decrease in proliferation.
  • the flow cytometry analysis results of HCT-116 cells treated with compound (1) at the 50 nM concentration demonstrate a decrease by approximately 50% of the intracellular H 2 O 2 concentration after 18 hours of treatment ( FIG. 9 a ). The effect observed is dose dependent ( FIG. 9 b ).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US14/435,768 2012-10-16 2013-10-14 N-substituted 3,4-bis (catechol) pyrrole compounds, and the preparation and use thereof in the treatment of cancer Expired - Fee Related US9546159B2 (en)

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FR1259868 2012-10-16
FR1259868A FR2996847B1 (fr) 2012-10-16 2012-10-16 Composes 3,4-bis(catechol)pyrrole-n-substitues, leur preparation et utilisation dans le traitement du cancer
PCT/EP2013/071445 WO2014060366A1 (fr) 2012-10-16 2013-10-14 Composes 3,4-bis(catechol)pyrrole-n-substitues, leur preparation et utilisation dans le traitement du cancer

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JP (1) JP6423349B2 (https=)
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CA (1) CA2888379A1 (https=)
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FR3022244B1 (fr) * 2014-06-17 2016-07-01 Centre Nat De La Rech Scient (Cnrs) Utilisation d'un nouveau compose 3-aryl-4-catechol-pyrrole-n-propanol et ses derives pour le traitement du cancer et des pathologies associees a une angiogenese excessive
CN121154883A (zh) * 2020-05-25 2025-12-19 医工瑞思(福建)工程研究中心有限公司 一种大面积创伤急救敷料套件及其使用方法

Citations (2)

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WO2000020411A1 (en) 1998-10-08 2000-04-13 Pharma Mar, S.A. Cytotoxic alkaloids (halitulin)
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WO2008064318A2 (en) * 2006-11-22 2008-05-29 University Of Medicine And Dentistry Of New Jersey Peripheral opioid receptor active compounds

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US6635656B1 (en) * 1998-10-08 2003-10-21 Pharma Mar, S.A. Cytotoxic alkaloids halitulin
WO2008064317A1 (en) 2006-11-22 2008-05-29 University Of Medicine And Dentistry Of New Jersey Lipophilic opioid receptor active compounds

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Borgulya et al., 104. Catechol-O-methyltransferase-Inhibiting Pyrocatechol Derivatives: Synthesis and Structure-Activity Studies, 72 Helvetica Chimica Acta 952-968 (1989).
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Koren-Goldshlager et al., Haliclorensin, a Novel Diamino Alkaloid from the Marine Sponge Haliclona tulearensis, 61 J. Nat. Prod. 282-284 (1998).
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CA2888379A1 (fr) 2014-04-24
JP2015534958A (ja) 2015-12-07
ES2608781T3 (es) 2017-04-17
FR2996847B1 (fr) 2014-12-05
JP6423349B2 (ja) 2018-11-14
AU2013331764B2 (en) 2017-11-16
EP2909171A1 (fr) 2015-08-26
WO2014060366A1 (fr) 2014-04-24
FR2996847A1 (fr) 2014-04-18
AU2013331764A1 (en) 2015-05-21
EP2909171B1 (fr) 2016-09-28
US20150344460A1 (en) 2015-12-03

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